Heart damage is common among patients hospitalized for the Covid-19 virus, leading many to wonder how the virus affects the heart. Now, researchers have discovered that the spike protein of the severe acute respiratory syndrome virus 2 (SARS-CoV-2) can cause heart muscle injury through the inflammatory process, according to preliminary research to be presented at the Scientific Sessions of Basic Cardiovascular Sciences 2022 of the American Heart Association.
The spike protein is found on the surface of SARS-CoV-2, the virus that causes Covid-19. The spike proteins attach to receptors known as angiotensin-converting enzyme 2 (ACE2) on target cells. The protein makes it easier for the virus to enter healthy cells, which is the first step in infection. In addition to infecting lungsthe virus can spread to other organs and cause more damage in the body, serious infection and, in some people, death.
“It is already known from a clinical point of view that Covid-19 infection can induce cardiac injury, however, what we do not know are the mechanistic details of how it occurs. What we suspect is that the spike protein has unknown pathological functions,” says Zhiqiang Lin, lead author of the study and assistant professor at the Utica Masonic Medical Research Institute (New York). “Our data show that the SARS-CoV-2 spike protein causes damage to the heart muscle. That is why it is important to get vaccinated and prevent this disease.”
“The host’s natural immunity is the first line of defense against pathogen invasion, and host cells heart muscle they have their own natural immune machinery. Activation of the body’s immune response is essential to fight the virus infection; however, this can also impair heart muscle cell function and even lead to cell death and heart failure,” Lin noted.
The researchers studied whether the SARS-CoV-2 spike protein activates the natural immune response in heart muscle cells. HCoV-NL63 is a coronavirus that infects the respiratory system without causing cardiac injury, although its spike protein also uses ACE2 to mediate virus entry. They studied the potential ability of both the SARS-CoV-2 spike protein and the NL63 spike protein to cause heart disease.
Their results showed that the SARS-CoV-2 spike protein activated the natural immune response in heart muscle cells and damaged the heart, but the NL63 spike protein did not.
“The fact that the spike protein of SARS-CoV-2 activate the natural immune response can you explain your etaken virulence compared to the other coronaviruses,” says Lin. “TLR4 signaling is the main pathway that activates the body’s natural immune response, and the SARS-CoV-2 spike protein activates TLR4, not the normal flu spike protein,” they explain.
To investigate the impact of the SARS-CoV-2 spike protein on the heart, the researchers cloned the SARS-CoV-2 spike protein and the NL63 spike protein into the viral vector AAV9. The AAV9 viral vector was administered to laboratory mice to activate the spike protein in heart muscle cells. They found that the AAV9-mediated spike protein of SARS-CoV-2, and not that of NL63, caused cardiac dysfunction, hypertrophic remodeling (enlargement), and cardiac inflammation.
The spike protein itself is highly inflammatory and can cause systemic inflammation leading to heart problems.
In laboratory tests with heart cells grown on plates, the researchers also observed that the spike protein from SARS-CoV-2 caused the heart muscle cells were much larger compared to cells without either spike protein. “We found direct evidence that the SARS-CoV-2 spike protein is toxic to heart muscle cells,” Lin says.
During this study, the researchers also examined a heart biopsy of a deceased patient with inflammation due to Covid-19. They detected the SARS-CoV-2 spike protein and the TLR4 protein in both heart muscle cells and other cell types. In contrast, these two proteins were absent in a biopsy from a healthy human heart. “That means that once the heart is infected with SARS-CoV-2, TLR4 signaling is activated,” Lin says. “In addition to directly damaging heart muscle cells, the spike protein itself is highly inflammatory and can cause systemic inflammation that indirectly causes heart problems.”
ACE2 is an important enzyme that controls blood pressure. SARS-CoV-2 infection can alter the function of ACE2, which in turn causes an increase in blood pressure and therefore damages the heart. SARS-CoV-2 can also damage the heart through other unknown pathways.
“Our study provides two pieces of evidence that the SARS-CoV-2 spike protein does not need ACE2 to damage the heart. First, we found that the SARS-CoV-2 spike protein damaged the hearts of laboratory mice. Unlike ACE2 in humans, ACE2 in mice does not interact with the SARS-CoV-2 spike protein, therefore, the SARS-CoV-2 spike protein did not damage the heart by directly disrupt the function of ACE2. Second, although both SARS-CoV-2 and NL63 coronaviruses use ACE2 as a receptor to infect cells, only the SARS-CoV-2 spike protein interacted with TLR4 and inflamed heart muscle cells. Therefore, our study presents a new pathological function of the spike protein of SARS-CoV-2, independent of ACE2”, explains Lin.
This research is the first step in determining whether the SARS-CoV-2 spike protein affects the heart. The researchers now plan to investigate how spike proteins from SARS-CoV-2 cause inflammation in the heart. There are two possible ways: the first is that the spike protein is expressed in virus-infected heart muscle cells and thus directly triggers inflammation; the second is that the spike protein of the virus is shed into the bloodstream, and circulating SARS-CoV-2 spike proteins damage the heart.